# Mechanisms of alloantibody production following renal transplantation

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $620,959

## Abstract

ABSTRACT
Acute and chronic antibody-mediated rejection (AMR) is a serious threat to the survival and function of
transplanted organs. The current options for AMR prevention and treatment are limited by the incomplete
understanding of the mechanisms underlying donor specific alloantibody (DSA) generation and pathogenic
functions. Whereas the production of high affinity isotype-switched DSA is typically associated with germinal
center formation by follicular B cells, the contribution of marginal zone (MZ) B cells to anti-donor responses
following transplantation has not been previously addressed. Our preliminary studies identify MZ B cells as
important players in orchestrating DSA responses and warrant detailed investigation of this B cell subset with an
ultimate objective of reducing humoral alloimmunity in transplant recipients.
Prolonged cold ischemia storage (CIS) of donor allografts and ensuing ischemia/reperfusion injury (IRI) remain
among leading risk factors for poor transplant outcome. Using a mouse model of kidney transplantation in which
allografts are subjected to 6 h CIS, we found that posttransplant inflammation specifically augments generation
of class II-reactive DSA that mediate allograft glomerular injury. These findings are highly relevant to clinical
studies revealing correlations between longer cold ischemia time, anti-class II DSA and late AMR in renal
transplant patients. However, the mechanisms by which posttransplant inflammation affects generation of
pathogenic class II DSA and the very source of donor class II antigens for B cell activation are poorly defined.
Based on our preliminary data, we hypothesize that IRI amplifies class II DSA production through the following
steps: 1) IRI up-regulates MHC class II expression on donor endothelial cells (EC) and EC release of class II
containing extracellular vesicles (EEVs); 2) spleen MZ B cells rapidly acquire circulating EEVs, produce early
DSA and facilitate further DSA production by FO B cells; and, 3) in addition to donor alloantigens, MZ B cell
activation is initiated and enhanced by DAMPs carried by graft-derived EVs as well as by systemic effects of IRI.
Therefore, targeting MZ B cell trafficking, activation and functions will inhibit generation of pathogenic class II
DSA and improve outcome of renal allografts subjected to prolonged CIS. We will test this hypothesis in three
Specific Aims:
Aim 1. To test whether ischemia/reperfusion injury (IRI) augments class II DSA by enhancing endothelial
extracellular vesicles (EEV) generation. Aim 2. To test the role of MZ B cells in DSA production following renal
transplantation. Aim 3. To investigate the contribution of MZ B cells in the generation of pathogenic class II DSA
after prolonged cold ischemia storage of renal allografts.
The proposed studies will fill several gaps in current knowledge of humoral alloimmune responses to
vascularized organ transplants and identify potential targets of therapeutic intervention to inhibit...

## Key facts

- **NIH application ID:** 10357956
- **Project number:** 5R01AI160740-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Anna Valujskikh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $620,959
- **Award type:** 5
- **Project period:** 2021-02-22 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357956

## Citation

> US National Institutes of Health, RePORTER application 10357956, Mechanisms of alloantibody production following renal transplantation (5R01AI160740-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10357956. Licensed CC0.

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